Untangling Direct and Domain-Mediated Interactions Between Nicotinic Acetylcholine Receptors in DHA-Rich Membranes
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At the neuromuscular junction (NMJ), the nicotinic acetylcholine receptor (nAChR) self-associates to give rise to rapid muscle movement. While lipid domains have maintained nAChR aggregates in vitro, their specific roles in nAChR clustering are currently unknown. In the present study, we carried out coarse-grained molecular dynamics simulations (CG-MD) of 1–4 nAChR molecules in two membrane environments: one mixture containing domain-forming, homoacidic lipids, and a second mixture consisting of heteroacidic lipids. Spontaneous dimerization of nAChRs was up to ten times more likely in domain-forming membranes; however, the effect was not significant in four-protein systems, suggesting that lipid domains are less critical to nAChR oligomerization when protein concentration is higher. With regard to lipid preferences, nAChRs consistently partitioned into liquid-disordered domains occupied by the omega-3 (\(\omega\)-3) fatty acid, docosahexaenoic acid (DHA); enrichment of DHA boundary lipids increased with protein concentration, particularly in homoacidic membranes. This result suggests dimer formation blocks access of saturated chains and cholesterol, but not polyunsaturated chains, to boundary lipid sites.
KeywordsNicotinic acetylcholine receptor (nAChR) Polyunsaturated fatty acids (PUFAs) Domain formation Lipid–protein interactions Lipid rafts Docosahexaenoic acid (DHA)
GB was supported by research Grants NSF MCB1330728 and NIH P01GM55876. GB and LM were also supported through a Grant from the Research Corporation for Scientific Advancement. This project was supported with computational resources from the National Science Foundation XSEDE program through allocation NSF-MCB110149, a local cluster funded by NSF-DBI1126052, the Rutgers University Office of Advanced Research Computing (OARC) and the Rutgers Discovery Informatics Institute (RDI2), which is supported by Rutgers and the State of New Jersey. We are grateful to Dr. Jérôme Hénin for his helpful suggestions throughout this study.
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Conflict of interest
The authors declare that they have no conflict of interest. This research was supported in part by the National Science Foundation, the National Institutes of Health, and the Research Corporation for Scientific Advancement.
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